tbuckley/cabot-search huggingface dataset:
TMIC-74. SPATIAL LANDSCAPE OF MELANOMA BRAIN METASTASES WITH AND WITHOUT PRE-SURGICAL IMMUNE CHECKPOINT BLOCKADE
Authors: Lu Sun, Lizhong Ding, Amber Monteleone, Linda Liau, Willy Hugo, Won Kim, Robert Prins
Journal: Neuro-Oncology (2023)

Abstract We recently characterized the immune populations of brain metastases samples with or without immune checkpoint blockade (ICB) treatment. In that study, we utilized single cell RNAseq (scRNAseq) and multiplex immunofluorescence (mIF) to demonstrate that ICB induced T cell infiltration and the migration of a unique MRC1+ macrophage subset from the perivascular space into the tumor parenchyma. However, scRNAseq’s tissue dissociation step loses spatial information of cells while mIF has low dimensionality, covering only a few markers for each tissue section. Thus, we applied sequencing-based Visium spatial transcriptomics (ST) to study the spatial architecture of melanoma brain metastases with/without ICB treatment and developed a pipeline that leverages public scRNAseq data as a reference to resolve fine-grained cell types on each Visium spot. ICB was associated with an increased CXCL13+ terminally exhausted T cell subset in close spatial proximity to tumor cells, suggestive of tumor specificity. ICB also reduced multiple MRC1+ macrophage subtypes in the blood vessel regions, supporting our mIF observation. Furthermore, we discovered that MRC1+ macrophages in close proximity to blood vessels expressed elevated TIMP1. TIMP1 is a known inhibitor of MMP9 that prevents ECM degradation and blood vessel damage, thus limiting T cell extravasation. In contrast, MRC1+ macrophages that migrated into the tumor had higher interferon activation and expressed CXCL9 and CXCL12 chemokines, which could recruit T cells via CXCR3 and CXCR4. Such findings could explain the increased T cell infiltration with ICB even in metastatic brain tumors. However, these MRC1+ macrophages also had an M2 signature and expressed multiple immune checkpoint ligands. Such data suggest these cells might also increase immunosuppressive interactions with T cells. In summary, our study reveals how ICB affects the spatial architecture and crosstalk of different cell types within melanoma brain metastases and will provide insights into new therapeutic strategies for brain metastases patients.
INNV-33. NEURO-ONCOLOGY VISITS AT HOME (NOVAH): A PILOT PROGRAM TO IMPROVE CARE FOR PATIENTS WITH BRAIN CANCER
Authors: April Eichler, Vanessa Merker, Liesel Von Imhof, Renee Pavlovich, Deborah Forst, Scott R Plotkin
Journal: Neuro-Oncology (2023)

Abstract Informational and care needs of brain cancer patients change rapidly and often outstrip the capacity of clinical encounters at key time points, including transitions from inpatient to home and times of high emotional and psychological needs (e.g., new diagnosis, disease progression). The existing care-model leaves little time for illness understanding and advance care planning (ACP) work. We piloted a home visit program (NoVaH) to assess feasibility and acceptability of specialty-level clinical support in the home at times of increased care needs. METHODS: Eligible patients were treated in the neuro-oncology practice of a single academic medical center, resided within 15 miles of the hospital, and were referred by clinic staff. Home visits were conducted by a neuro-oncologist one half-day per week and scheduled longitudinally according to need, in parallel with primary outpatient visits. 9 family caregiver interviews were conducted virtually and analyzed by a qualitative researcher using rapid analysis methods to synthesize findings across predetermined, deductive categories. RESULTS: 18 patients referred from outpatient (61%) or inpatient service (39%) completed ≥ 1 home visit. Most patients had glioblastoma (78%). 59 home visits took place over 12 months (median per patient 2, range 1-8). A first life-sustaining treatment order form was completed by 10/18 patients (56%). Among 10 patients who died, place of death was home (50%), skilled nursing facility (20%), inpatient hospice (20%), or hospital (10%); 90% were enrolled in hospice at time of death. Caregivers voiced specific benefits such as ability to receive care patients would have otherwise forgone, improved communication about illness understanding and ACP, and enhanced sense of control and ability to digest prognostic information compared with office setting. CONCLUSIONS: Neuro-oncology home visits are feasible and acceptable to patients with brain cancer and represent an innovative way to provide patient-centered cancer care at times of transition and complex decision-making.
CTIM-38. NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS
Authors: Philipp Karschnia, Isabel Arrillaga-Romany, April Eichler, Deborah Forst, Elizabeth Gerstner, Justin T Jordan, Ina Ly, Scott R Plotkin, Nancy Wang, Maria Martinez-Lage, Sebastian F Winter, Joerg-Christian Tonn, Kai Rejeski, Louisa von Baumgarten, Daniel Cahill, Brian V Nahed, Ganesh M Shankar, Jeremy S Abramson, Jeffrey A Barnes, Areej El-Jawahri, Ephraim P Hochberg, P Connor Johnson, Jacob D Soumerai, Ronald W Takvorian, Yi-Bin Chen, Matthew J Frigault, Jorg Dietrich
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS. METHODS We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period. RESULTS Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.
PATH-49. COMPREHENSIVE RNA-SEQ ANALYSIS REVEALS NOVEL SUBTYPES OF MENINGIOMAS AND PREDICTS PATIENT OUTCOME.
Authors: H Nayanga Thirimanne, Damian AlmironBonnin, Nicholas Nuechterlein, Sonali Arora, Matt Jensen, Carolina Da Silva Parada, Frank Szulzewsky, Collin English, William Chen, Philipp Sievers, Farshad Nassiri, Justin Wang, Akash Patel, David Raleigh, Gelareh Zadeh, Kenneth Aldape, Tiemo J Klisch, Felix Sahm, Manuel Ferreira, Eric Holland
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Meningiomas are the most common intracranial tumor in humans. While most tumors are benign, some are malignant and ultimately lethal. Current grading systems based on WHO grade do not provide adequate risk stratification, therefore, better characterizations of the biology of aggressive meningiomas are needed. METHOD: We obtained 12 datasets from 9 institutions and 5 countries in North America, Europe and Asia and combined them with ~300 tumors sequenced from the University of Washington to create a set of ~1300 meningioma tumors. Raw sequencing data was aligned to hg38, batch corrected and then dimension reduction of normalized counts was performed to create a UMAP landscape. Differential expression analysis and gene set enrichment analysis were performed to elucidate the underlying biology of meningioma subtypes. RESULTS The analysis revealed nine distinct meningioma subtypes through unsupervised clustering. Clinical metadata, DNA sequencing, copy number alterations, and gene-fusion data effectively correlated with these identified clusters. These subtypes exhibited specific biological signatures. Notably, regional distribution of time to recurrence identified subtypes as well as intra-cluster differences of meningiomas with varying patient outcomes. The most aggressive subtype, characterized by higher WHO grades, frequent tumor recurrences, and shorter time to recurrence, exhibited elevated proliferation rates and RNA expression resembling embryonic limb development. To facilitate clinical applications, we developed a cross-validated nearest-neighbors-based algorithm that accurately mapped new patients onto this UMAP landscape, achieving a remarkable 95% accuracy. CONCLUSION Our study highlights the utility of RNA sequencing in discerning meningioma heterogeneity and provides a valuable tool in predicting tumor biology and patient prognosis. The integration of our UMAP landscape with patient data offers an effective approach for personalized treatment strategies.
NIMG-49. INTRAOPERATIVE 5-ALA INTENSITY ANALYSIS OF GLIOMA USING IMAGE J
Authors: Takashi Kon, Yusuke Kobayashi, Katsuyoshi Shimizu, Tohru Mizutani, Yosuke Sato
Journal: Neuro-Oncology (2023)

Abstract PURPOSE: The 5 aminolevulinic acid (5-ALA) is used for intraoperative tumor visualization in neurosurgery. We hypothesized that glioma may vary in malignancy according to the brightness of 5-ALA. We quantified the brightness of 5-ALA and compared it with the pathological results of glioma. MATERIALS AND METHODS: From 2019 to 2023, we investigated 35 glioma patients who underwent surgery with 5-ALA. Twenty-three cases of glioblastoma (GBM), four cases of anaplastic astrocytoma (AA), three cases of oligodendroglioma (OL), one case of anaplastic oligodendroglioma (AO), and four cases of low grade glioma (LGG) were examined. The pathological diagnosis was based on classification of WHO 2016. The 5-ALA was administered before surgery, and the 5-ALA brightness were quantified. RESULTS: In GBM, the mean brightness was 134.5 ± 65.4, except for one negative case. AA showed the mean brightness with 180.5 ± 51.6. Three cases of OL showed the mean brightness with 78.6 ± 32.7. AO showed the brightness with 153. All LGGs showed negative in the brightness. CONCLUSION: The 5-ALA showed higher brightness in GBM , AA, AO and negative in LGG. In the future, we will accumulate cases and add further studies.
TMIC-51. THE RELEASE OF INFLAMMATORY CYTOKINES ARE REGULATED BY PYK2 SIGNALING IN GBM CELLS
Authors: Emely Morales-Colón, Lilia Kucheryavykh
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly aggressive brain cancer that is typically fatal within a year of diagnosis. Previous research has shown a positive relationship between the activation of a protein called proline-rich non-receptor tyrosine kinase (Pyk2) in GBM cells in addition to the expression of cytokines by tumor-infiltrating myeloid (TIM cells). Leading to a sustained increase in the expression levels of monocyte chemoattractant protein 1 (CCL2), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL10, IL12, and vascular endothelial growth factor (VEGF), as well as an increase in the CD86+/CD206+ TIM population. We hypothesize that Pyk2 signaling in GBM cells is involved in the regulation of the release of inflammatory cytokines, which in turn suppresses the immune response in the tumor microenvironment. We used CRISPR/Cas9 knockout Pyk2 (Pyk2KO) and wild type (Pyk2WT) GL261 mouse glioma cells in this study. Analysis of the cytokines present in the cell culture medium conditioned by Pyk2KO and Pyk2WT cells identified a decrease in the release of CCL2 and CCL5 in the Pyk2KO cells compared to the Pyk2WT cells. RT-PCR analysis of myeloid cell population, isolated from Pyk2WT and Pyk2KO tumors in the GL261-C57Bl/6 GBM model, identified a significant down-regulation of key pro-tumorigenic factors such as CCL2, CCL12, CCL5, tumor necrosis factor (TNF), VEGF and epidermal growth factor (EGF) in the Pyk2KO tumors compared to the Pyk2WT tumors. Additionally, flow cytometry analysis revealed a reduction in myeloid-derived suppressor cells (MDSCs), an increase in lymphoid dendritic cells (DC), and up-regulation in TNF/IFNg expressing and antigen-specific CD8+ T cells in Pyk2KO tumors. Furthermore, a significant decrease in pro-tumorigenic Ly6C+/CD206+ and an up-regulation of inflammatory Ly6C+/CD86+ myeloid cells were found in the Pyk2KO tumors. These findings suggest that Pyk2KO tumors display an immunocompetent microenvironment with enhanced phagocytic and cytotoxic function compared to Pyk2WT tumors. NIH Grant 1SC1GM122691 and PRSTRT2022 supported this study
CNSC-06. REDIRECTING IMMUNOSUPPRESSIVE GLIOMA MICROENVIRONMENT THROUGH PHARMACOLOGICAL INTERVENTION TARGETING NEURONAL ACTIVITY
Authors: Takahide Nejo, Saritha Krishna, Akane Yamamichi, Christian Jimenez, Senthilnath Lakshmanachetty, Jacob Young, Su Phyu, Payal Watchmaker, Shawn Hervey-Jumper, Hideho Okada
Journal: Neuro-Oncology (2023)

Abstract Recent single-cell RNA-sequencing analyses have revealed a strong association between glioma-neuronal circuit remodeling and regional immunosuppression. Subsequent preclinical investigations using syngeneic tumor models demonstrated that genetic disruption of circuit assembly genes, including Thrombospondin-1 (TSP-1/Thbs1) in GBM cells suppressed synaptogenesis, excitatory neurotransmitter ligand and receptor density in addition to neuronal activities while simultaneously restoring inflammatory responses, indicating glioma-neuron-immune cross talk. However, the underlying mechanisms and directions of causality remain unclear. Here we test the hypothesis that tumor-derived synaptogenic factors directly reprogram the tumor immune microenvironment (“model 1”). Alternatively, tumor intrinsic neuronal activity may indirectly regulate adaptive immunity (“model 2”). In this study, we performed in-vitro bone-marrow-derived macrophage (BMDM) reprogramming assays evaluating various stimulation conditions and in-vivo experiments evaluating the effect of neuronal activity-oriented therapy on the tumor-associated macrophages (TAMs). Our in-vitro assays demonstrated that, secreted factors from mouse neonatal cortical neurons (not tumor-derived synaptogenic factors) induced an anti-inflammatory, M2-like phenotype of BMDMs, corroborating the proposed model 2. This M2-inducing effect was inhibited when the neuronal activities were suppressed pharmacologically, using perampanel (PER), a noncompetitive inhibitor of neuronal AMPA-type glutamate receptors. Direct treatment of BMDMs with PER did not affect the polarization patterns, further supporting the M2-inducing effect of glutamatergic excitatory neuronal signals. In in-vivo syngeneic orthotopic tumor models, treatment with PER significantly prolonged survival compared to the non-treated group (27.5 [PER] vs. 23 days [control], p = 0.01). Flow cytometric analysis of brain-infiltrating leukocytes showed that TAMs isolated from PER-treated mice exhibited a more proinflammatory M1-like polarization compared to the control group (median M1/M2 ratio, 1.2 [PER] vs. 0.7 [control], p = 0.004), which explained the improved prognosis. Collectively, these findings unveil novel immunosuppression mechanisms induced by glioma-neuronal circuit remodeling and the resulting excitatory neuronal signals, and potential therapeutic vulnerabilities that could be targeted in combination with cancer immunotherapy.
PATH-42. UNCOVERING AN ASSOCIATION BETWEEN OLIGODENDROGLIOMA AND THE HUMAN PAPILLOMAVIRUS (HPV) THROUGH MOLECULAR SUBPOPULATION ANALYSIS USING NETRAAI
Authors: Bessi Qorri, Mike Tsay, Josh Spiegel, Douglas Cook, Joseph Geraci
Journal: Neuro-Oncology (2023)

Abstract Oligodendrogliomas (OGs) are a rare subset of primary brain tumors, accounting for approximately 5% of all brain tumors. While the etiology of OG has yet to be fully characterized, genomic heterogeneity is linked to clinical heterogeneity with variability in progression and survival. Currently, OGs are stratified into three molecular subtypes based on IDH mutation and 1p/19q co-deletion with additional molecular heterogeneity related to EGFR, PTEN, 10q deletion, and several other markers observed among 1p/19q co-deleted OGs. Using a public OG dataset, we assembled a set consisting of 156 primary OG tumors, 14 primary glioma samples, and 9 normal samples profiled using mRNA expression arrays. Using NetraAI, a novel machine learning platform, we identified three OG patient subpopulations based on survival and differentially expressed genes. Examining low- versus high-grade OG, we identified two subpopulations: (1) 26 low-grade and 21 high-grade OGs characterized by higher RPS6KV1 expression, and (2) 6 low-grade and 61 high-grade OGs characterized by higher LFNG expression. A third subpopulation emerged examining 1p/19p co-deletion, consisting of 60 no co-deletion and 3 co-deletion OGs characterized by higher HDAC1 expression. These driving genes have a common link to human papillomavirus (HPV) infection based on functional genomic analysis. HDAC1 is a histone deacetylase involved in gene expression regulation, LFNG is implicated in the Notch signaling pathway, and RPS6KB1 is a kinase regulating protein synthesis and cell growth. We hypothesize that concomitant HPV infection may negatively impact OG prognosis, warranting further investigation into the precise molecular interactions linking HPV infection to clinical outcomes. Furthermore, exploring the link between HPV infection and vaccination to OG outcomes on a population basis may provide valuable insights. The identification of these subpopulations, not previously described by other groups, demonstrates the utility of the NetraAI approach in uncovering subpopulations with potential implications in developing targeted therapies for OG.
TMET-18. METABOLOMIC APPROACH TO IDENTIFICATION OF PROGNOSTIC BIOMARKERS OF GLIOBLASTOMA
Authors: John Paul Aboubechara, Yin Allison Liu, Oliver Fiehn, Ruben Fragoso, Han Lee, Jonathan Riess, Rawad Hodeify, Orin Bloch, Orwa Aboud
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma, the most common malignant primary brain tumor, is associated with poor prognosis despite aggressive treatment. Alterations in cellular metabolism driven by acquired mutations contribute to tumor progression and recurrence. Metabolic changes in plasma can serve as potential biomarkers, offering insights into treatment response and prognostic value. In this prospective study, we enrolled 36 patients with isocitrate dehydrogenase (IDH) wild type glioblastoma (18 MGMT methylated, 16 MGMT unmethylated, 2 MGMT unknown) and performed untargeted metabolomics on patient plasma before and after surgery, as well as before and after concurrent chemoradiation. Our analysis focused on examining changes in 157 metabolites throughout each stage of treatment. We conducted correlations between metabolite levels and treatment stages, as well as associations between metabolite levels and disease progression or overall survival to identify clinically relevant biomarkers. Preliminary results demonstrate positive correlation between specific metabolite levels at the time of diagnosis and eventual overall survival. Notably, metabolites such as trans-4-hydroxyproline, ribose, pipecolinic acid, phenol, kynurenine, inositol-4-monophosphate, indole-3-propionic acid, glucose, arachidonic acid, 5-methoxytryptamine, and 3-aminopiperidine-2,6-dione show significant positive correlations (p&amp;lt; 0.05) with overall survival. However, no metabolites exhibited negative associations with overall survival. Ongoing analysis will further explore the relationship between metabolite levels at different treatment stages and survival outcomes. By future planned machine learning techniques integration to our study, we aim to enhance our understanding of the metabolomic changes associated with treatment response and prognosis. This study represents a step toward unraveling the metabolomic alterations in glioblastoma patients throughout treatment. Although the underlying metabolic pathways and potential shared mechanisms are not yet fully understood, the identified metabolites associated with overall survival hold promise as potential biomarkers for prognosis. Furthermore, the integration of machine learning techniques will provide a more comprehensive understanding of the complex metabolic changes in glioblastoma.
MODL-06. THE GUT MICROBIOTA OF BRAIN TUMOR PATIENTS CAN IMPACT IMMUNOTHERAPY EFFICACY IN A PRECLINICAL MODEL OF GLIOMA
Authors: Donggeon Kim, Sujith Sarvesh, Olivia Valbak, Olivia Backan, Dongquan Chen, Casey Morrow, Etty Benvensite, Burt Nabors, Mahesh Bekal, Antonio Dono, Yoshua Esquenazi, Peter Forsyth, Hsiang-Hsuan Michael Yu, Nikhil Khushalani, Kathleen Egan, Braden McFarand
Journal: Neuro-Oncology (2023)

Abstract Combination immune checkpoint inhibitors (ICI) can affect durable response in melanoma brain metastases (MBM) but have largely been ineffective for the treatment of glioblastoma (GBM), a primary brain tumor. Recent studies in animal models and humans have suggested that the microbe composition of the gut can influence the effectiveness of ICI in melanoma and other cancers. Our central hypothesis is that the gut microbiome can influence immunotherapy responsiveness for GBM patients. We obtained microbiome (stool) samples from GBM and MBM patients prior to beginning any treatment or surgical interventions. We then transplanted these microbiome samples into gnotobiotic mice to create humanized microbiome mice. We transplanted two GBM patients and two MBM patients microbiome samples to create 4 unique patient-derived humanized microbiome mouse lines (GBM1, GBM2, MBM1, and MBM2). Using 16s ribosomal RNA microbiome sequencing, we found that each patient-derived microbiome mouse line had a unique microbiome composition as measured by relative abundance and diversity of species. Mice from each line were then intracranially injected with GL261 murine glioma cells and treated with the ICI anti-PD-1 or isotype control. We found that MBM1 and GBM2 mice were resistant to anti-PD-1 and did not display prolonged survival with anti-PD-1 treatment. However, GBM1 and MBM2 mice were positive responders to anti-PD-1 and displayed significantly prolonged survival compared to isotype control. Additional microbiome sequencing analyses are ongoing that will reveal positive microbiome profiles among these patient-derived lines, and additional GBM and MBM patient-derived microbiome lines are being created and tested for immunotherapy efficacy. Ultimately, understanding how certain microbial communities can enhance the effectiveness of immunotherapy may lead to the development of new approaches that include modification or transplantation of microbe communities in GBM patients for increased therapeutic impact.